Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide, accounting for 23% (1.38 million) of the total new cancer cases and 14% (458,400) of the total cancer deaths in 2008. About half the breast cancer cases and 60% of the deaths are estimated to occur in economically developing countries. The rate of incidence observed in France is among the strongest in Europe and is in constant increase.
20-30% of primary human breast cancers are due to the deregulated expression of ErbB2/HER2 or the expression of mutated or truncated forms of ErbB2/HER2: it represents approximately 8,000 patients a year in France and 450,000 patients a year worldwide. ErbB2/HER2 overexpression or abnormally activated is associated with a poor diagnosis, tumors with deregulated ErbB2/HER2 having been shown to grow faster, to be more aggressive and to be less sensitive to chemotherapy or to hormonotherapy. ErbB2/HER2 deregulation is also associated with disease recurrence. Then, so called ErbB2/HER2 dependent cancers constitute a very specific group of cancer of an utmost interest in public health. Only 25% of the treated patients respond to the actual therapies. The actual strategies aiming at targeting the extracellular domain (anti-HER2 antibody therapies Herceptin/trastuzumab and pertuzumab from Roche/Genentech, USA) or the kinase activity of the receptor (small molecule tyrosine kinase inhibitors, lapatinib/Tykerb, GSK, USA) have proven to exhibit limited actions. In particular, these molecules have no potent action on the mutated and truncated forms of HER2. Concerning trastuzumab, 66% to 88% of treated patients never respond to treatment (i.e. present a “primary resistance”) and among the one-third of the treated patients that respond to this agent, a disease progression on average in less than one year (i.e. develop an “acquired resistance”) is generally observed. Trastuzumab emtansine (also known as T-DM1) has been recently developed and is a novel antibody-drug conjugate that contains the antibody trastuzumab and DM1, a microtubule-inhibitory maytansinoid, linked through a thioether bond. Upon binding to HER2, T-DM1 is then internalized and degraded in lysosomes to release DM1-containing cytotoxic components which cause inhibition of cell division and cell growth, and eventually cell death. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance, by mechanisms related to trastuzumab resistance combined to some related to DM1 resistance (upregulation of multi-drug resistance transporters or altered microtubule dynamics for examples) (Li G et al. Trastuzumab-DM1: mechanisms of action and mechanisms of resistance 2010).
Treatments with small molecule tyrosine kinase inhibitors (e.g. lapatinib) are often associated to increased toxicity due to a non-specific inhibition of promiscuous ErbB and non-ErbB kinases by these agents, limiting the extent to which they can be used safely. The median duration of response to lapatinib was less than one year, and a majority of trastuzumab-pre-treated patients (˜80%) failed to respond.
The efficacy of current treatments is limited by the development of therapeutic resistance mainly attributed to the expression of p95HER2, as this highly active truncated form of HER2 lacks the recognition site for trastuzumab. However, therapeutic resistance to HER2 specific treatment or occurrence of metastasis can also be due to point mutations in HER2 protein sequence: for instance, K753E mutation and resistance to lapatinib or V777L and resistance to trastuzumab [Zuo et al. Clin Cancer Res 2016, 22(19), 4859-4869].
There is therefore an urgent need for the development of alternative approaches that would specifically target ErbB2/HER2 to reduce the risk of toxicity and also work efficiently on mutated and truncated forms of ErbB2 resistant to the current treatments of ErbB2 cancers.
It was previously shown that interaction of the FERM domain of the ERM family members (Ezrin, Moesin, Radixin) and of the related member Merlin with the juxtamembrane domain of ErbB2 prevents ErbB2 activation. This interaction stabilizes ErbB2 in a catalytically repressed state by exerting a molecular constraint on the juxtamembrane domain of ErbB2, restricting access of the kinase domain to substrate tyrosines (WO/2011/036211). A High Throughput Screening assay based on the disruption of the interaction between the juxtamembrane domain of HER2 and the Ezrin FERM domain was then set up to identify small molecule inhibitors which will behave as the FERM domain to actively block ErbB2 (FR1452246).